Tricyclic benzodiazepine derivates, their preparation, and pharmaceutical compositions containing them

ABSTRACT

Tricyclic compounds of the formula: ##STR1## wherein R 1  1 is hydrogen or an organic group, 
     R 2  is aryl which may have suitable substituent(s), 
     R 3  is hydrogen or an acyl group and 
     A is lower alkylene, 
     and pharmaceutically acceptable salts thereof which are useful as a medicament.

TECHNICAL FIELD

This invention relates to new tricyclic compounds and pharmaceuticallyacceptable salts thereof which are useful as a medicament.

BACKGROUND ART

Some tricyclic compounds have been known as described, for example, inEP 0360079Al.

DISCLOSURE OF INVENTION

This invention relates to new tricyclic compounds and pharmaceuticallyacceptable salts thereof.

More particularly, it relates to new tricyclic compounds andpharmaceutically acceptable salts thereof which are cholecystokinin(CCK) antagonists and therefore useful as therapeutical and/orpreventive agents for emesis, pancreatitis, disorders of appetiteregulatory systems, pain, insulinoma, gastroparesis, carcinoma ofpancreas, gallbladder disease (e.g. acute cholecystitis, calculus,etc.), disorders associated with intestinal smooth muscle hyperactivity(e.g. irritable bowel syndrome, sphincter spasm, etc.),hyperinsulinemia, dyspepsia, nausea, etc.

The tricyclic compounds of this invention can be represented by thefollowing formula (I): ##STR2## wherein R¹ is hydrogen or an organicgroup,

R² is aryl which may have suitable substituent(s),

R³ is hydrogen or an acyl group, and

A is lower alkylene.

According to the present invention, the new tricyclic compounds (I) canbe prepared by the processes which are illustrated in the followingscheme. ##STR3## wherein R¹, R² and A are each as defined above,

R⁴ is an organic group,

R_(a) ³ is an acyl group,

R_(b) ³ is an acyl group having a protected amino group and

R_(c) ³ is an acyl group having an amino group.

The starting compound (II) is novel and can be prepared by the followingprocesses. ##STR4## wherein R¹, R², R⁴ and A are each as defined above,

X¹ is halogen,

X² is halogen,

R⁵ is lower alkyl and

X³ is halogen.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfoante,formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acidsalt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), asalt with an amino acid (e.g. arginine, aspartic acid, glutamic acid,etc.), and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unlessotherwise indicated.

The term "higher" is intended to mean 7 to 20 carbon atoms, unlessotherwise indicated.

Suitable "organic group" may include lower alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl,tert-pentyl, hexyl, etc.),

lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl,etc.),

lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl,1 or 2 or 3 butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or5-hexynyl, etc.),

aryl (e.g., phenyl, naphthyl, etc.),

ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl,phenylpropyl, etc.) and the like.

Suitable "aryl" may include phenyl, naphthyl and the like.

Suitable "substituent" in the term "aryl which may have suitablesubstituent(s)" may include halogen, amino, lower alkoxy, mono(or di ortri)halo(lower)alkyl and the like.

Suitable "halogen" and "halogen moiety" in the term "mono(or di ortri)halo(lower)alkyl" may include chlorine, bromine, fluorine andiodine.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy,hexyloxy and the like.

Suitable "lower alkyl" and "lower alkyl moiety" in the term "mono(or dior tri)halo(lower)alkyl" may include straight or branched one having 1to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like,preferably one having 1 to 4 carbon atoms(s).

Suitable "acyl" may include carbamoyl, aliphatic acyl group and acylgroup containing an aromatic ring, which is referred to as aromaticacyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows: Carbamoyl;Aliphatic acyl such as lower or higher alkanoyl (e.g. formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl,icosanoyl, etc.); lower or higher alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl,heptyloxycarbonyl, etc.); lower or higher alkanesulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.); lower or higher alkoxysulfonyl(e.g. methoxysulfonyl, ethoxysulfonyl, etc.); or the like;

Aromatic acyl such as

aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.);

ar(lower)alkanoyl [e.g. phenyl(lower)alkanoyl (e.g. phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl,phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g. naphthylacetyl,naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];

ar(lower)alkenoyl [e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl,phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl,etc.), naphthyl(lower)alkenoyl (e.g. naphthylpropenoyl,naphthylbutenoyl, naphthylpentenoyl, etc.), etc.];

ar(lower)alkoxycarbonyl [e.g. phenyl(lower)alkoxycarbonyl (e.g.benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g. phenoxycarbonyl,naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl (e.g., phenoxyacetyl,phenoxypropionyl, etc.); arylcarbamoyl (e.g. phenylcarbamoyl,naphthylcarbamoyl, etc.); arylthiocarbamoyl (e.g. phenylthiocarbamoyl,etc.); arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.);arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.); or thelike;

Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g. thienylacetyl, thienylpropanoyl, thienylbutanoyl,thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl,tetrazolylacetyl, etc.); heterocyclic(lower)alkenoyl (e.g.heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl (e.g.thiazolylglyoxyloyl, thienylglyoxyloyl, etc.); or the like; in whichsuitable heterocyclic moiety in the terms "heterocycliccarbonyl","heterocyclic(lower)alkanoyl", heterocyclic(lower)alkenoyl and"heterocyclicglyoxyloyl" as mentioned above means, in more detail,saturated or unsaturated, monocyclic or polycyclic heterocyclic groupcontaining at least one hetero-atom such as an oxygen, sulfur, nitrogenatom and the like.

And especially preferable heterocyclic group may be heterocyclic groupsuch as

unsaturated 3 to 8-membered more preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4-nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3to 8-membered (more preferably 5 or 6-membered)heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s), for example pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated condensedheterocyclic group containing 1 to 4 nitrogen atom(s), for example,indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, cinnolinyl, quinoxalinyl, etc.;unsaturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; saturated 3 to 8-membered [more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferable 5 or6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to8-membered (more preferably 5 or 6-membered) heteromonocyclic groupcontaining 1 to 2 sulfur atom(s), for example, thienyl,dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensedheterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogenatom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;unsaturated 3 to 8-membered (more preferably 5 to 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.; unsaturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2sulfur atom(s), for example, dihydrooxathiinyl, etc.; unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atom(s), forexample, benzothienyl, benzodithiinyl, etc.; unsaturated condensedheterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s),for example, benzoxathiinyl, etc. and the like.

The acyl moiety as stated above may have one to ten, same or different,suitable substituent(s) such as halogen (e.g. fluorine, chlorine,bromine or iodine), hydroxy, nitro, lower alkyl (e.g. methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.),amino, protected amino, lower alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, t-butoxy, pentyloxy, hexyloxy, etc.), carboxy, protectedcarboxy, N,N-di(lower)alkyl-amino(lower)alkyl (e.g.N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dimethylaminoethyl,N,N-diethylaminoethyl, N,N-dipropylaminoethyl, N,N-dimethylaminopropyl,N,N-diethylaminopropyl, N,N-dipropylaminopropyl, N,N-dibutylaminomethyl,N,N-dipentylaminomethyl, N,N-dihexylaminomethyl, etc.),hydroxyimino(lower)alkyl (e.g. hydroxyiminomethyl, hydroxyiminoethyl,hydroxyiminopropyl, hydroxyiminobutyl, hydroxyiminopentyl,hydroxyiminohexyl, etc.), arylimino(lower)alkyl [e.g.phenylimino(lower)alkyl (e.g. phenyliminomethyl, phenyliminoethyl,phenyliminopropyl, phenyliminobutyl, phenyliminopentyl,phenyliminohexyl, etc.), etc.], acyl such as lower alkanoyl (e.g.formyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, etc.), mono(ordi or tri)halo(lower)alkyl, arylamino(e.g. phenylamino, etc.), or thelike.

Suitable "protected amino" may include acylamino and the like.

Suitable "acyl moiety" in the term "acylamino" can be referred to theones as mentioned above.

Suitable "protected carboxy" may include esterified carboxy and thelike.

Suitable example of the ester moiety of an esterified carboxy may be theones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propylester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester,pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which mayhave at least one suitable substituent(s), for example, loweralkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester, 1(or 2 or 3 or4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2 or3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester, 1(or2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester,2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1(or2)-pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)alkylester (e.g. 2-mesylethyl ester, etc.), mono(or di ortri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy(lower)alkylester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester,1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkylester, or (5-lower alkyl 2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynylester, propynyl ester, etc.); ar(lower)alkyl ester which may have atleast one suitable substituent(s) such as mono(or di ortri)-phenyl(lower)alkyl ester which may have at least one suitablesubstituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzylester, phenethyl ester, trityl ester, benzhydryl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which mayhave at least one suitable substituent(s) (e.g. phenyl ester,4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester,mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.

Suitable "lower alkylene" may include straight or branched one having 1to 6 carbon atom(s), such as methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene or the like, preferablyone having 1 to 4 carbon atoms(s).

Preferred embodiments of the object compound (I) are as follows:

R¹ is lower alkyl [more preferably (C₁ -C₄)alkyl, most preferablymethyl],

R² is aryl (more preferably phenyl) which may have one to three suitablesubstituent(s) [more preferably phenyl which may have halogen, mostpreferably halophenyl],

R³ is hydrogen; or an organic carboxylic or an organic carbamic acyl,for example, heterocycliccarbonyl [more preferably unsaturated 5 or6-membered heteromonocycliccarbonyl in which heteromonocyclic groupcontains 1 to 4 nitrogen atom(s) or unsaturated condensedheterocycliccarbonyl in which heterocyclic group contains 1 to 4nitrogen atom(s), most preferably pyridylcarbonyl, indolylcarbonyl,quinolylcarbonyl, isoquinolylcarbonyl, cinnolinylcarbonyl orquinoxalinylcarbonyl], aroyl (more preferably benzoyl or naphthoyl)which may have one to three (more preferably one or two) suitablesubstituent(s) [more preferably benzoyl which may have one or twohalogen, or naphthoyl; most preferably dihalobenzoyl or naphthoyl],arylcarbamoyl (more preferably phenylcarbamoyl) which may have one tothree suitable substituent(s) [more preferably phenylcarbamoyl which mayhave lower alkyl, most preferably lower alkylphenylcarbamoyl], orar(lower)alkanoyl (more preferably phenyl(lower)alkanoyl)which may haveone to three suitable substituent(s) [more preferablyphenyl(lower)alkanoyl which may have amino or protected amino, mostpreferably phenyl(lower)alkanoyl having amino or acylamino], and

A is lower alkylene [more preferably (C₁ -C₄)alkylene, most preferablyethylene].

The processes for preparing the object compound (I) of the presentinvention are explained in detail in the following.

Process 1

The compound (Ia) or a salt thereof can be prepared by reacting thecompound (II) or a salt thereof with the compound (III) or a saltthereof.

Suitable salts of the compounds (Ia) and (II) can be referred to theones as exemplified for the compound (I).

Suitable salts of the compound (III) can be referred to the acidaddition salts as exemplified for the compound (I).

This reaction is usually carried out in a solvent such as water alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, methylene chloride, ethylene chloride, chloroform,diethyl ether, acetonitrile, or any other solvent which does notadversely affect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process 2

The compound (Ib) or a salt thereof can be prepared by subjecting thecompound (Ia) or its reactive derivative at the amino group or a saltthereof to acylation reaction.

Suitable acylating agent to be used in the present acylation reactionmay include the compound of the formula:

    R.sub.a.sup.3 --OH                                         (XV)

(wherein R_(a) ³ is as defined above.) or its reactive derivative or asalt thereof.

Suitable reactive derivative at the amino group of the compound (Ia) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (Ia) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (Ia) with a silyl compound such asN,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound (Ia) with phosphorustrichloride or phosgene, and the like.

Suitable salts of the compounds (Ia) and (XV) can be referred to theones as exemplified for the compound (I).

Suitable reactive derivative of the compound (XV) may include an acidhalide, an acid anhydride, an activated amide, an activated ester,isocyanate, and the like. The suitable example may be an acid chloridean acid azide; a mixed acid anhydride with an acid such as substitutedphosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoricacid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethylester, dimethyliminomethyl [(CH₃)₂ N⁺ ═CH--] ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with aN-hydroxy compound (e.g. N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole,N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.);substituted or unsubstituted aryl isocyanate; substituted orunsubstituted aryl isothiocyanate; and the like. These reactivederivatives can optionally be selected from them according to the kindof the compound (XV) to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely influence the reaction. These conventional solvents mayalso be used in a mixture with water.

When the compound (XV) is used in free acid form or its salt form in thereaction, the reaction is preferably carried out in the presence of aconventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride;triphenylphosphine; 2-ethyl-7-hydroxybenzisoxasolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotirazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, orthe like. The reaction temperature is not critical, and the reaction isusually carried out under cooling to heating.

Process 3

The compound (Ia) or a salt thereof can be prepared by subjecting thecompound (Ib) or a salt thereof to deacylation reaction. Suitable methodof this reaction may include conventional one such as hydrolysis,reduction and the like.

(i) For Hydrolysis

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], the hydroxide orcarbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. Theelimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

(ii) For reduction

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound(e.g. chromium chloride, chromium acetate, etc.) and an organic orinorganic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts(e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reducedcopper, Raney copper, Ullman copper, etc.) and the like. The reductionis usually carried out in a conventional solvent which does notadversely influence the reaction such as water, methanol, ethanol,propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

Process 4

The compound (Id) or a salt thereof can be prepared by subjecting thecompound (Ic) or a salt thereof to elimination reaction of the aminoprotective group. This reaction can be carried out in a similar mannerto that of aforementioned Process 3.

The processes for preparing the starting compound (II) are explained inthe following.

Process A - 1

The compound (VI) or a salt thereof can be prepared by reacting acompound (IV) or a salt thereof with a compound (V) or a salt thereof inaccordance with the method disclosed in the Preparation 1 describedlater or a similar manner thereto.

Process A - 2

The compound (VIII) or a salt thereof can be prepared by reacting acompound (VI) or a salt thereof with a compound (VII).

This reaction can be carried out in accordance with the method disclosedin the Preparation 2 described later or a similar manner thereto.

Process A - 3

The compound (X) or a salt thereof can be prepared by reacting acompound (VIII) or a salt thereof with a compound (IX) or a saltthereof.

This reaction can be carried out in accordance with the method disclosedin the Preparation 3 described later or a similar manner thereto.

Process A - 4

The compound (XII) or a salt thereof can be prepared by reacting acompound (X) or a salt thereof with a compound (XI).

This reaction can be carried out in the presence or absence of aconventional solvent.

The reaction temperature is not critical and the reaction is usuallycarried out at ambient temperature, under warming or under heating.

Process A - 5

The compound (XIII) or a salt thereof can be prepared by subjecting acompound (XII) or a salt thereof to hydrolysis.

The hydrolysis can be carried out in the presence of a base, andsuitable base may be the inorganic base such as alkali metal hydroxide(e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metalhydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkalimetal carbonate (e.g. sodium carbonate, potassium carbonate, etc.),alkaline earth metal carbonate (e.g. magnesium carbonate, calciumcarbonate, etc.) or the like.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, diethyl ether or any other solvent which does notadversely affect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process A - 6

The compound (II) or a salt thereof can be prepared by reacting acompound (XIII) or a salt thereof with a compound (XIV).

This reaction is usually carried out in the presence of a base such astri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), di(lower)alkylaniline (e.g.,dimethylaniline, etc.) or the like.

This reaction is usually carried out in a solvent such as benzene,N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylenechloride, chloroform, diethyl ether or any other solvent which does notadversely affect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

The object compound (I) and pharmaceutically acceptable salts thereofare CCK antagonists and therefore useful as therapeutical agents foremesis, pancreatitis, etc. Further, it is expected that the objectcompound (I) and pharmaceutically acceptable salts thereof have gastrinantagonism and are useful as therapeutical and/or preventive agents forulcers, excess gastric secretion, zollinger-Ellison Syndrome, etc.

In order to show the utility of the object compound (I), pharmacologicalactivity of the representative compound thereof is shown in thefollowing.

[I] Test compound

(6RS)-1-Methyl-5-oxo-6-(2-indolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline

[II] Test:

[¹²⁵ I ] CCK-8 binding to rat pancreatic membranes

Test Method

(i) Membrane preparation

Rats were killed by a blow on the head and bled to death. Whole pancreas(about 0.7 g) was removed, minced in a small quantity of 50 mM Tris-HClbuffer (pH 7.4), and homogenized in 30 vol: of the buffer by a polytronhomogenizer. The homogenate was centrifuged at 30000×g (16000 rpm) for10 min. The pellet was then resuspended in the same buffer by aglass-teflon homogenizer and recentrifuged at 30000×g for 10 min. Thisprocedure (washings) was repeated twice more. The final pellet(membrane) was suspended in incubation medium (see below) so as toobtain a final protein concentration of 2 mg/ml. All manipulations weredone at 0°-4° C.

(ii) Receptor binding assay

The composition of incubation medium was as follows: 50 mM Tris-HCl (pH7.4), 5 mM MgCl₂, 5 mM dithiothreitol (DTT), 0.14 mg/ml bacitracin, and0.2% bovine serum albumin (BSA). Freshly prepared membranes (200 μgprotein) were incubated for 30 min under shaking at 37° C. in plastictubes in 500 μl of incubation medium with 50 pM ¹²⁵ I-CCK-8 in thepresence or absence of test compound (1×10⁻⁸ M). To determine thenon-specific binding, CCK-8 at 1 μM was added. Each assay was performedin duplicate. Reaction mixture was filtered through a Whatman GF/B glassfilter to stop the reaction. After washing the filter with 50 mMTris-HCl (pH 7.4) buffer containing 0.1% BSA, the radioactivity of thefilter was counted. Non-specific binding was subtracted from totalbinding to yield specific binding. The effect of test compound wasexpressed as % inhibition of specific ¹²⁵ I-CCK-8 binding.

Test Result

Inhibition (%): 95.7

The object compound (I) or pharmaceutically acceptable salts thereof canusually be administered to mammals including human being in the form ofa conventional pharmaceutical composition such as capsule,micro-capsule, tablet, granule, powder, troche, syrup, aerosol,inhalation, solution, injection, suspension, emulsion, suppository orthe like.

The pharmaceutical composition of this invention can contain variousorganic or inorganic carrier materials, which are conventionally usedfor pharmaceutical purpose, such as excipient (e.g. sucrose, starch,mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate,calcium carbonate, etc.), binding agent (cellulose, methyl cellulose,hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic,polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch,carboxymethyl cellulose, calcium salt of carboxymethyl cellulose,hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calciumphosphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate,talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citric acid,mentol, glycine, organge powders, etc.), preservative (e.g. sodiumbenzoate, sodium bisulfite, methylparaben, propylparaben, etc.),stabilizer (e.g. citric acid, sodium citrate, acetic acid, etc.),suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminumstearate, etc.), dispersing agent, aqueous diluting agent (e.g. water),base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum,etc.).

The effective ingredient may usually be administered with a unit doseof. 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the abovedosage may be increased or decreased according to age, weight,conditions of the patient or the administering method.

The following preparations and examples are given only for the purposeof illustrating the present invention in more detail.

Preparation 1

To a solution of 2N-boron trichloride in benzene (82 ml) was dropwiseadded a solution of 1-methyl-1,2,3,4-tetrahydroquinoxaline (19.87 g) intoluene (40 ml) under stirring. To the resultant mixture was dropwiseadded a solution of 2-fluorobenzonitrile (19.50 g) in toluene (30 ml) atambient temperature under stirring and the mixture was stirred for 1.5hours under the same condition. To this mixture was added aluminumtrichloride (19.65 g) and the mixture was refluxed for 16 hours. Water(30 ml) and 2N-hydrochloric acid (100 ml) were added to the reactionmixture under cooling in an ice-bath and the mixture was refluxed for2.5 hours. After the mixture was allowed to stand at ambient temperaturefor several hours, ethyl acetate was added to the mixture. The organiclayer was separated, washed with water twice, dried over magnesiumsulfate and evaporated under reduced pressure. The residue waschromatographed on silica gel with an eluent of n-hexane. The fractionscontaining the desired product were combined and evaporated. Theresultant red oil was crystallized with diisopropyl ether, collected byfiltration and dried to give1-methyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (11.71 g).

mp: 90°-92° C.

IR (Nujol): 3275, 1608, 1520, 1480, 1458, 1442, 1380, 1305, 1275, 1240,1203, 1127, 978, 755, 726 cm⁻¹

NMR (CDCl₃, δ): 2.89 (3H, s), 3.23 (2H, t, J=2.6 Hz), 3.71 (2H, m),6.36-6.77 (3H, m), 7.1-7.4 (4H, m), 9.28 (1H, broad s)

Preparation 2

To a solution of1-methyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (11.99 g) andpyridine (4.04 g) in methylene chloride (200 ml) was dropwise added asolution of bromoacetyl bromide (5.09 ml) in methylene chloride (10 ml)under stirring at a temperature below 10° C. and the mixture was stirredfor 3 hours at the same temperature. The reaction mixture was washedwith water twice and dried. Removal of the solvent afforded viscous oil.The viscous oil was triturated with diisopropyl ether, collected byfiltration, washed with diisopropyl ether and dried to give1-methyl-4-bromoacetyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline(17.18 g).

IR (Nujol): 1675 (sh), 1662, 1607, 1586, 1500, 1460, 1402, 1335, 1295,1212, 769, 751 cm⁻¹

NMR (CDCl₃, δ): 3.25 (3H, s), 3.73 (2H, s), 2.7-4.6 (4H, m), 6.6-7.8(7H, m)

Preparation 3 ##STR5##

To a solution of sodium hydroxide (7.92 g) and hydroxylaminehydrochloride (15.75 g) in a mixture of water (80 ml) and ethanol (80ml) was added a suspension of1-methyl-4-bromoacetyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline(17.18 g) in ethanol (40 ml) portionwise under stirring at 50° C. Themixture was stirred for 2 hours at the same temperature and cooled in anice-bath for 1 hour. The resultant precipitate was collected byfiltration, washed with a small amount of cold ethanol and dried to give1-methyl-5-oxo-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline7-oxide (7.47 g).

mp: 205°-206° C. (dec.)

IR (Nujol): 1662, 1609, 1583, 1532, 1493, 1451, 1403, 1335, 1197, 1062,887, 788, 750 cm⁻¹

NMR (DMSO-d₆, δ): 3.01 (3H, s), 3.0-3.1 (1H, m), 3.4-3.5 (2H, m), 4.39(1H, d, J=6.3 Hz), 4.75 (1H, dt, J=4.6 Hz, 13 Hz), 4.89 (1H, d, J=6.3Hz), 6.16 (1H, d, J=3.3 Hz), 6.80 (1H, d, J=3.3 Hz), 7.04 (1H, t, J=4.0Hz), 7.2-7.6 (4H, m)

MASS: m/e=325 (M⁺)

Preparation 4

A suspension of1-methyl-5-oxo-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline7-oxide (7.44 g) in acetic anhydride (50 ml) was stirred for 45 minutesat 95°-100° C. The mixture was cooled in an ice-bath and addeddiisopropyl ether (50 ml). The mixture was stirred under cooling in anice-bath for 1 hour. The resultant precipitate was collected byfiltration and washed with cold diisopropyl ether to afford(6RS)-1-methyl-5-oxo-6-acetoxy-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline(7.58 g) as yellow crystalline powder.

mp: 201°-202° C.

IR (Nujol): 1741, 1690, 1600, 1584, 1455, 1400, 1373, 1229, 1114, 1060,765, 748 cm⁻¹

NMR (DMSO-d₆, δ): 2.20 (3H, s), 3.02 (3H, s), 2.9-3.1 (1H, m), 3.3-3.5(2H, m), 4.69 (1H, d, J=6.3 Hz), 5.83 (1H, s), 6.39 (1H, d, J=3.5 Hz),6.92 (1H, d, J=3.5 Hz), 7.0-7.6 (5H, m)

MASS: m/e=367 (M⁺)

Preparation 5

To a suspension of(6RS)-1-methyl-5-oxo-6-acetoxy-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(7.55 g) in ethanol (190 ml) was added 1N-sodium hydroxide (20.6 ml)under stirring at ambient temperature. The clear solution was stirredfor 10 minutes. The mixture was adjusted to pH 6 with 6N-hydrochloricacid and ethanol was removed under reduced pressure. To the resultantmixture was added water (100 ml) and the mixture was adjusted to pH 7.0with a saturated aqueous solution of sodium bicarbonate. The resultantyellow precipitate was collected by filtration, washed with water anddried over phosphorous pentoxide in desiccator under reduced pressure togive(6RS)-1-methyl-5-oxo-6-hydroxy-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline(6.54 g).

mp: 225°-227° C. (dec.)

IR (Nujol): 3375, 1664, 1610, 1578, 1491, 1551, 1428, 1388, 1373, 1332,1152, 1027, 880, 778, 742 cm⁻¹

NMR (DMSO-d₆, δ): 2.99 (3H, s), 2.9-3.1 (1H, m), 3.4-3.5 (2H, m), 4.73(1H, dt, J=5.0 Hz, 1.4 Hz), 4.84 (1H, s), 6.3-7.6 (8H, m)

MASS: m/e=325 (M⁺)

EXAMPLE 1 ##STR6##

To a suspension of(6RS)-1-methyl-5-oxo-6-hydroxy-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(1.63 g) and diisopropylethylamine (0.97 g) in methylene chloride (15ml) was added dropwise a solution of mesyl chloride (0.86 g) inmethylene chloride (1 ml) under stirring and cooling in an ice-bath. Themixture was stirred for 15 minutes under the same conditions and for 30minutes at ambient temperature. The reaction mixture containing(6RS)-1-methyl-5-oxo-6-mesyloxy-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxalinewas poured into a mixture of 28% aqueous ammonia (8.2 ml) andacetonitrile (16.5 ml) at ambient temperature with a vigorous stirringand the mixture was stirred for 1 hour. From the reaction mixture,methylene chloride and acetonitrile were removed under reduced pressure.Water was added to the residual aqueous mixture. The mixture wasextracted with chloroform twice. The chloroform layer was combinedwashed with water twice and dried over magnesium sulfate. Removal of thesolvent afforded viscous brown oil, which was chromatographed on silicagel with an eluent of a mixture of chloroform and methanol (100:1). Thefractions containing the desired product were combined and evaporated togive(6RS)-1-methyl-5-oxo-6-amino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(0.88 g) as orange oil.

NMR (CDCl₃, δ): 2.41 (2H, broad s), 3.01 (3H, s), 2.6-3.2 (1H, m),3.3-3.7 (2H, m), 4.58 (1H, s), 3.9-5.0 (1H, m), 6.4-7.7 (7H, m)

MASS: m/e=324 (M⁺)

EXAMPLE 2 ##STR7##

To a mixture of(6RS)-1-methyl-5-oxo-6-amino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(0.73 g), indole-2-carboxylic acid (0.36 g) and 1-hydroxybenzotriazole(0.30 g) in N,N-dimethylformamide (10 ml) were addedN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.43 g)and triethylamine (0.23 g) under stirring and cooling in an ice-bath.The mixture was stirred at ambient temperature for 2.0 hours. Thereaction mixture was poured into a mixture of ice-water (100 ml) andethyl acetate (30 ml) under vigorous stirring. The resultant precipitatewas collected by filtration and washed with a small amount of coldethanol and ethyl acetate to give yellow crystalline powder (0.58 g).This powder was vigorously stirred in water to remove crystallinesolvent for 5 days, collected by filtration and dried over phosphoruspentoxide under reduced pressure to give(6RS)-1-methyl-5-oxo-6-(2-indolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(0.52 g).

mp: 275°-280° C. (dec.)

NMR (CDCl₃, δ): 3.05 (3H, s), 3.0-3.2 (1H, m), 3.4-3.6 (2H, m), 4.96(1H, broad d, J=6.4 Hz), 5.92 (1H, d, J=4 Hz), 6.5-8.1 (13H, m), 9.78(1H, s)

MASS: m/e=467 (M⁺)

EXAMPLE 3

The following compounds were obtained according to a similar manner tothat of Example 2.

(1)(6RS)-1-Methyl-5-oxo-6-(3-quinolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline

mp: 246°-251° C. (dec.)

IR (Nujol): 3390, 1675, 1660, 1610, 1500, 1375, 1340, 1228, 1020, 884,774, 775, 720 cm⁻¹

NMR (DMSO-d₆, δ): 3.05 (3H, s), 3.0-3.2 (1H, m), 3.4-3.6 (2H, m), 4.77(1H, broad d, J=6.2 Hz), 5.71 (1H, d, J=4.0 Hz), 6.44 (1H, d, J=3.4 Hz),6.96 (1H, d, J=3.4 Hz), 7.0-8.2 (9H, m), 9.06 (1H, d, J=1.0 Hz), 9.37(1H, d, J=1.0 Hz), 10.08 (1H, d, J=4.0 Hz)

MASS: m/e=479 (M⁺)

(2)(6RS)-1-Methyl-5-oxo-6-(2-naphthylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline

mp: 142°-145° C. (dec.)

IR (Nujol): 3200, 1660 (sh), 1656, 1625, 1600, 1495, 1400, 1375, 1337,1286, 871, 780, 763, 745 cm⁻¹

NMR (DMSO-d₆, δ): 3.05 (3H, s), 3.0-3.2 (1H, m), 3.4-3.6 (2H, m), 4.77(1H, broad d, J=6.2 Hz), 5.72 (1H, d, J=6.0 Hz), 6.44 (1H, d, J=3.5 Hz),6.95 (1H, d, J=3.5 Hz), 7.0-8.1 (11H, m), 8.71 (1H, s), 9.76 (1H, d,J=4.0 Hz)

MASS: m/e=478 (M⁺)

(3)(6RS)-1-Methyl-5-oxo-6-(3,4-dichlorobenzoylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline

mp: 215°-218° C.

IR (Nujol): 3200, 1691, 1647, 1610, 1595, 1530, 1375, 1345, 1280, 1183,876, 781, 749 cm⁻¹

NMR (DMSO-d₆, δ): 3.04 (3H, s), 3.0-3.1 (1H, m), 3.4-3.6 (2H, m), 4.74(1H, broad d, J=6.1 Hz), 5.62 (1H, d, J=4.0 Hz), 6.42 (1H, d, J=3.5 Hz),6.94 (1H, d, J=3.5 Hz), 7.0-8.3 (9H, m), 9.96 (1H, d, J=4.0 Hz)

MASS: m/e=497 (M⁺)

(4) (6RS)-1-Methyl-5-oxo-6-nicotinoylamino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxalinedihydrochloride

mp: 185°-190° C. (dec.)

IR (Nujol): 3600-3100, 2700-1900, 1670, 1630, 1610. 1580 cm⁻¹

NMR (DMSO-d₆, δ): 3.04-3.50 (6H, m), 4.75 (1H, d, J=12.3 Hz), 5.65 (1H,d, J=7.6 Hz), 6.48 (1H, d, J=7.3 Hz), 6.94-8.09 (7H, m), 8.89 (1H, d,J=8.1 Hz), 9.03 (1H, d, J=5.3 Hz), 9.36 (1H, s), 10.35 (1H, d, J=7.6 Hz)

MASS: m/e=429 (M⁺ -73)

(5)(6RS)-1-Methyl-5-oxo-6-(1-isoquinolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxalinehydrochloride

mp: 160°-170° C. (dec.)

IR (Nujol): 3550-3100, 2700-2000, 1660, 1605, 1580 cm⁻¹

NMR (DMSO-d₆, δ): 2.95-3.16 (1H, m), 3.05 (3H, s), 3.39-3.51 (2H, m),4.80 (1H, d, J=12.4 Hz), 5.65 (1H, d, J=7.9 Hz), 6.48 (1H, d, J=6.9 Hz),6.95-8.18 (10H, m), 8.67 (1H, d, J=5.6 Hz), 9.19 (1H, d, J=8.5 Hz), 9.86(1H, d, J=7.9 Hz)

MASS: m/e=479 (M⁺ -37), 462

(6)(6RS)-1-Methyl-5-oxo-6-(4-cinnolinylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline

mp: 228°-230° C.

IR (Nujol): 3200, 1690, 1660, 1610, 1595, 1535 cm⁻¹

NMR (DMSO-d₆, δ): 2.95-3.63 (6H, m), 4.82 (1H, d, J=12.4 Hz), 5.72 (1H,d, J=7.6 Hz), 6.47 (1H, d, J=7.0 Hz), 6.99-8.60 (10H, m), 9.48 (1H, s),10.41 (1H, d, J=7.6 Hz)

MASS: m/e=480 (M⁺)

(7)(6RS)-1-Methyl-5-oxo-6-(2-quinoxalinyl)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline

mp: 278°-280° C.

IR (Nujol): 3350, 1670, 1610, 1575, 1515 cm⁻¹

NMR (DMSO-d₆, δ): 3.04-3.50 (6H, m), 4.79 (1H, d, J=12.4 Hz), 5.64 (1H,d, J=7.9 Hz), 6.47 (1H, d, J=7.2 Hz), 6.95-8.36 (10H, m), 9.53-9.60 (2H,m)

MASS m/e=480 (M⁺)

(8)(6S)-1-Methyl-5-oxo-6-(2-indolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline

mp: 187°-194° C. (dec.)

[α]_(D) ³⁰ =79.33° (C=0.808, CHCl₃)

IR (Nujol): 3370, 3205, 1678, 1640, 1532, 1490, 1458, 1338, 1216, 1190,1120, 810, 745 cm⁻¹

NMR (DMSO-d₆, δ): 3.04 (3H, s), 3.0-3.1 (1H, m), 3.3-3.5 (2H, m), 4.76(1H, broad d, J=6.2 Hz), 5 68 (1H, d, J=4.1 Hz), 6.4-7.7 (12H, m), 9.57(1H, d, J=4.1 Hz), 11.64 (1H, s)

MASS: m/e=467 (M⁺)

(9)(6R)-1-Methyl-5-oxo-6-(2-indolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline

mp: 187°-210° C. (dec.)

[α]_(D) ³⁰ =-72.77° (C=0.808, CHCl₃)

IR (Nujol): 3370, 3200, 1676, 1638, 1531, 1489, 1456, 1336, 1220, 1189,1118, 808, 745 cm⁻¹

NMR (DMSO-d₆, δ): 304 (3H, s), 3.0-3.1 (1H, m), 3.3-3.5 (2H, m), 4.76(1H, broad d, J=6.2 Hz), 5.68 (1H, d, J=4.1 Hz), 6.4-7.7 (12H, m), 9.57(1H, d, J=4.1 Hz), 11.64 (1H, s)

MASS: m/e=467 (M⁺)

EXAMPLE 4

To a solution of(6RS)-1-methyl-5-oxo-6-amino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(0.7 g) in tetrahydrofuran (11 ml) was added m-tolyl isocyanate (0.32 g)under stirring at ambient temperature. The mixture was stirred for 1.5hours under the same conditions. The solvent was removed under reducedpressure to give powder, which was purified by column chromatography onsilica gel with an eluent of chloroform. The fractions containing thedesired product were combined and evaporated. The residue was pulverizedwith diisopropyl ether, collected by filtration, washed with diisopropylether and dried under reduced pressure to give(6RS)-1-methyl-5-oxo-6-[N'-(m-tolyl)ureido]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(0.8 g).

mp: 242°-245° C.

IR (Nujol): 3300, 1675, 1640, 1610, 1555 cm⁻¹

NMR (DMSO-d₆ δ): 2.24 (3H, s), 2.27 (1H, s), 2.91-3.60 (6H, m), 4.75(1H, d, J=12.4 Hz), 5.33 (1H, d, J=7.2 Hz), 6.41 (1H, d, J=7.6 Hz),6.73-7.56 (10H, m), 8.96 (1H, s)

EXAMPLE 5

A mixture of(6RS)-1-methyl-5-oxo-6-amino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline(9.27 g), N-t-butoxycarbonyl-L-phenylalanine (7.96 g),1-hydroxybenzotriazole (3.97 g),N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.64 g)and triethylamine (2.97 g) in N,N-dimethylformamide (95 ml) was stirredfor 2 hours at ambient temperature. To the reaction mixture were addedethyl acetate (200 ml) and water (150 ml) under vigorous stirring. Themixture was adjusted to pH 8 with a saturated aqueous solution of sodiumbicarbonate. The separated organic layer and the extract from theaqueous layer with ethyl acetate (200 ml) were combined and washed withwater twice. The dried extract was evaporated under reduced pressure togive crude organge oil (17.58 g) of a mixture of(6R)-1-methyl-5-oxo-6-[((2S)-2-tertbutoxycarbonylamino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxalineand(6S)-1-methyl-5-oxo-6-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxaline.

NMR (CDCl₃, δ): 1.39, 1.40 (9H, s & s), 3.04, 3.05 (3H, s & s), 3.0-3.7(6H, m), 4.57 (1H, broad s), 4.86, 4.93 (1H, broad q & broad q), 5.01(1H, broad s), 5.58, 5.59 (1H, d & d, J=4 Hz), 6.5-7.7 (12H, m)

MASS: m/e=571 (M⁺)

EXAMPLE 6

A solution of a mixture (17.2 g) of(6R)-1-methyl-5-oxo-6-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalineand(6S)-1-methyl-5-oxo-6-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalinein ethyl acetate (350 ml) was saturated with dried hydrogen chloride.The mixture was stirred for 3 hours at ambient temperature. Excesshydrogen chloride was removed as much as possible by bubbling with astream of nitrogen. The resultant solution was extracted with water andwith diluted hydrochloric acid. The combined aqueous extract wasneutralized with a aqueous solution of sodium bicarbonate. An oilyproduct was extracted with ethyl acetate twice and washed with water.After the extract was dried over magnesium sulfate, the solvent wasremoved under reduced pressure to give yellow oil (11.98 g) of a mixtureof(6R)-1-methyl-5-oxo-6-[((2S)-2-amino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalineand(6S)-1-methyl-5-oxo-6-[((2S)-2-amino-3-phenylpropanoyl)-amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline.

EXAMPLE 7

A mixture (11.98 g) of(6R)-1-methyl-5-oxo-6-[((2S)-2-amino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino-[1,7,6-de]quinoxalineand(6S)-1-methyl-5-oxo-6-[(2S)-2-amino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalinewas subjected to column chromatography on silica gel with an eluent ofchloroform. The fractions containing the one isomer were combined andevaporated to give an yellow crystal of(6S)-1-methyl-5-oxo-6-[(2S)-2-amino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline(4.12 g).

mp: 195°-198° C.

NMR (CDCl₃, δ): 1.55 (2H, s), 2.80 (1H, dd, J=5 Hz, 6.8 Hz), 3.05 (3H,s), 3.13 (1H, dd, J=1.7 Hz, 5 Hz), 3.3-3.8 (4H, m), 4.92 (1H, dq, J=6.3Hz, 1 Hz), 5.66 (1H, d, J=4.3 Hz), 6.5-7.7 (12H, m), 8.98 (1H, d, J=4.3Hz)

The fractions containing the other isomer were combined and evaporatedto give orange oil of(6R)-1-methyl-5-oxo-6-[((2S)-2-amino-3-phenylpropanoyl)-amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline(4.89 g).

NMR (CDCl₃, δ): 1.56 (2H, s), 2.67 (1H, dd, J=5 Hz, 6.8 Hz), 3.05 (3H,s), 3.13 (1H, dd, J=1.8 Hz, 6.2 Hz), 3.3-3.8 (4H, m), 4.94 (1H, dq,J=5.3 Hz, 1 Hz), 5.64 (1H, d, J=4.3 Hz), 6.5-7.7 (12H, m), 9.0 (1H, d,J=4.2 Hz)

EXAMPLE 8

To a solution of(6S)-1-methyl-5-oxo-6-[((2S)-2-amino-3-phenylpropanoyl)amino]-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline(3.85 g) in methylene chloride (70 ml) was added phenyl isothiocyanate(1.32 g) under stirring at ambient temperature. The methylene chloridewas distilled under stirring at 80° C. To the residue was addedmethylene chloride (70 ml). This procedure was repeated four times. Fromthe reaction mixture, methylene chloride was removed completely underreduced pressure. To the residue was added trifluoroacetic acid (50 ml)and the mixture was warmed under stirring at 50° C. for 20 minutes.After removal of the solvent in vacuo, the residue was subjected tocolumn chromatography on silica gel with an eluent of a mixture ofchloroform and methanol (40:1→20:1). The fractions containing thedesired product were combined and washed with an aqueous solution ofsodium bicarbonate. After drying, solvent was removed in vacuo to give(6S)-1-methyl-5-oxo-6-amino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline(2.99 g).

[α]_(D) ²⁹ =97.94° (C=0.54, MeOH)

NMR (CDCl₃, δ): 2.40 (2H, broad s), 3.04 (3H, s), 3.01-3.2 (1H, m),3.3-3.65 (2H, m), 4.58 (1H, s), 4.9-5.0 (1H, m), 6.45-7.7 (7H, m)

EXAMPLE 9

The following compound was obtained according to a similar manner tothat of Example 8.

(6R)-1-Methyl-5-oxo-6-amino-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline

[α]_(D) ²⁹ =-89.77° (C=0.54, CH₃ OH)

NMR (CDCl₃, δ): 2.46 (2H, broad s), 3.04 (3H, s), 3.01-3.2 (1H, m), 4.59(1H, s), 4.9-5.0 (1H, m), 6.45-7.7 (7H, m)

We claim:
 1. A compound of the formula: ##STR8## wherein R¹ is hydrogen,or an organic group selected from the group consisting of lower alkyl,lower alkenyl, lower alkynyl, phenyl, naphthyl and phenyl(lower)alkyl,R²phenyl or naphthyl, each of which may have from 1 to 3 substituentsselected form the group consisting of halogen, amino, lower alkoxy andmon, di or tri halo(lower)alkyl, R³ is hydrogen, or an acyl groupselected from the group consisting of carbamoyl, C1 to C20 alkanoyl, C2to C20 alkoxycarbonyl, C1 to C20 alkanesulfonyl, C1 to C20alkoxysulfonyl, benzoyl, naphthoyl, phenyl(lower)alkanoyl,naphthyl(lower)alkanoyl, phenyl(lower)alkenoyl, naphthyl(lower)alkenoyl,phenyl(lower)alkoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl,phenylcarbamoyl, naphthylcarbamoyl, phenylthiocarbamoyl,phenylglyoxyloyl, naphthylglyoxyloyl, benzenesulfonyl,heterocyclicglyoxyloyl, heterocyclic(lower)alkanoyl,heterocyclic(lower)alkenoyl, and heterocycliccarbonyl wherein saidheterocyclic moiety is selected form the group consisting of pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, indolyl, isoindolyl, indolinyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, cinnolinyl, quinoxalinyl, oxazolyl, isoxazolyl,oxadiazolyl, morpholinyl, sydnonyl, benzoxazolyl, benzoxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl,thienyl, dihydrodithiinyl, dihydrodithionyl, benzothiazolyl,benzothiadiazolyl, furyl, dihydrooxathiinyl, benzothienyl,benzodithiinyl and benzoxathiinyl, and said acyl group may have from 1to 10 substituents selected from the group consisting of halogen,hydroxy, nitro, lower alkyl, amino, lower alkoxycarbonylamino, loweralkoxy, carboxy, N,N-di(lower)alkylamino(lower)alkyl,hydroxyimino(lower)alkyl, phenylimino(lower)alkyl, lower alkanoyl, mono,di or tri halo(lower)alkyl and phenylamino, and A is ethylene,and apharmaceutically acceptable salt thereof.
 2. A compound of claim 1,whereinR¹ is hydrogen or lower alkyl, and R³ is hydrogen,heterocycliccarbonyl wherein said heterocyclic moiety is selected fromthe group consisting of pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl,tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl,indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, cinnolinyl, quinoxalinyl,oxazolyl, isoxazolyl, oxadiazolyl, morpholinyl, sydnonyl, benzoxazolyl,benzoxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,dihydrothiazinyl, thiazolidinyl, thienyl, dihydrodithiinyl,dihydrodithionyl, benzothiazolyl, benzothiadiazolyl, furyl,dihydrooxathiinyl, benzothienyl, benzodithiinyl and benzoxathiinyl,benzoyl which may have from 1 to 3 substituents selected from the groupconsisting of halogen, hydroxy, nitro, lower alkyl, amino, loweralkoxycarbonylamino, lower alkoxy, carboxy,N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl,phenylimino(lower)alkyl, lower alkanoyl, mono, di or trihalo(lower)alkyl and phenylamino, phenylcarbamoyl which may have from 1to 3 substituents selected from the group consisting of halogen,hydroxy, nitro, lower alkyl, amino, lower alkoxycarbonylamino, loweralkoxy, carboxy, N,N-di(lower)alkylamino(lower)alkyl,hydroxyimino(lower)alkyl, phenylimino(lower)alkyl, lower alkanoyl, mono,di or tri halo(lower)alkyl and phenylamino, or phenyl(lower)alkanoylwhich may have from 1 to 3 substituents selected from the groupconsisting of halogen, hydroxy, nitro, lower alkyl, amino, loweralkoxycarbonylamino, lower alkoxy, carboxy,N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl,phenylimino(lower)alkyl, lower alkanoyl, mono di or tri halo(lower)alkyland phenylamino.
 3. A compound of claim 2, whereinR² is phenyl which mayhave halogen and R³ is hydrogen, pyridylcarbonyl, indolylcarbonyl,quinolylcarbonyl, isoquinolylcarbonyl, cinnolinylcarbonyl,quinoxalinylcarbonyl, benzoyl which may have one or two halogen,naphthoyl, phenylcarbamoyl which may have lower alkyl, orphenyl(lower)alkanoyl which may have amino or lower alkoxycarbonylamino.
 4. A compound of claim 3, whereinR³ is hydrogen,pyridylcarbonyl, indolylcarbonyl, quinolylcarbonyl, isoquinolylcarbonyl,cinnolinylcarbonyl, quinoxalinylcarbonyl, dihalobenzoyl, naphthoyl,lower alkylphenylcarbamoyl, or phenyl(lower)alkanoyl having amino orlower alkoxycarbonylamino.
 5. A compound of claim 4, whereinR¹ is loweralkyl, R² is halophenyl, R³ is indolylcarbonyl and A is (C₁-C₄)alkylene.
 6. A compound of claim 5, which is(6S)-1-methyl-5-oxo-6-(2-indolylcarbonylamino)-8-(2-fluorophenyl)-2,3,5,6-tetrahydro-1H-[1,4]-diazepino[1,7,6-de]quinoxaline.7. A process for preparing a compound of the formula: ##STR9## whereinR¹ is hydrogen, or an organic group selected from the group consistingof lower alkyl, lower alkenyl, lower alkynyl, phenyl, naphthyl andphenyl(lower)alkyl,R³ is phenyl or naphthyl, each of which may have from1 to 3 substituents selected from the group consisting of halogen,amino, lower alkoxy and mono di or tri halo(lower)alkyl, R³ is hydrogen,or an acyl group selected from the group consisting of carbamoyl, C1 toC20 alkanoyl, C2 to C20 alkoxycarbonyl, C1 to C20 alkanesulfonyl, C1 toC20 alkoxysulfonyl, benzoyl, naphthoyl, phenyl(lower)alkanoyl,naphthyl(lower)alkanoyl, phenyl(lower)alkenoyl, naphthyl(lower)alkenoyl,phenyl(lower)alkoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl,phenylcarbamoyl, naphthylcarbamoyl, phenylthiocarbamoyl,phenylglyoxyloyl, naphthylglyoxyloyl, benzenesulfonyl,heterocyclicglyoxyloyl, heterocyclic(lower)alkanoyl,heterocyclic(lower)alkenoyl and heterocycliccarbonyl wherein saidheterocyclic moiety is selected form the group consisting of pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, indolyl, isoindolyl, indolinyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, cinnolinyl, quinoxalinyl, oxazolyl, isoxazolyl,oxadiazolyl, morpholinyl, sydnonyl, benzoxazolyl, benzoxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl,thienyl, dihydrodithiinyl, dihydrodithionyl, benzothiazolyl,benzothiadiazolyl, furyl, dihydrooxathiinyl, benzothienyl,benzodithiinyl and benzoxathiinyl, and said acyl group may have from 1to 10 substituents selected from the group consisting of halogen,hydroxy, nitro, lower alkyl, amino, lower alkoxycarbonylamino, loweralkoxy, carboxy, N,N-di(lower)alkylamino(lower)alkyl,hydroxyimino(lower)alkyl, phenylimino(lower)alkyl, lower alkanoyl, monodi or tri halo(lower)alkyl and phenylamino, and A is ethylene, or a saltthereof,which comprises (1) reacting a compound of the formula:##STR10## wherein R¹, R² and A are each as defined above, and R⁴ is anorganic group, selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, phenyl, naphthyl and phenyl(lower)alkyl or asalt thereof with a compound of the formula:

    NH.sub.3

or a salt thereof to give a compound of the formula: ##STR11## whereinR¹, R² and A are each as defined above, or a salt thereof, or (2)subjecting a compound of the formula: ##STR12## wherein R¹, R² and A areeach as defined above, or its reactive derivative at the amino group, ora salt thereof to acylation reaction to give a compound of the formula:##STR13## wherein R¹, R² and A are each as defined above, R_(a) ³ is anacyl group selected from the group consisting of carbamoyl, C1 to C20alkanoyl, C2 to C20 alkoxycarbonyl, C1 to C20 alkanesulfonyl, C1 to C20alkoxysulfonyl, benzoyl, naphthoyl, phenyl(lower)alkanoyl,naphthyl(lower)alkanoyl, phenyl(lower)alkenoyl, naphthyl(lower)alkenoyl,phenyl(lower)alkoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl,phenylcarbamoyl, naphthylcarbamoyl, phenylthiocarbamoyl,phenylglyoxyloyl, naphthylglyoxyloyl, benzenesulfonyl, heterocyclicglyoxyloyl, heterocyclic(lower)alkanoyl, heterocyclic(lower)alkenoyl,and heterocyclic carbonyl wherein said heterocyclic moiety is selectedform the group consisting of pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,cinnolinyl, quinoxalinyl, oxazolyl, isoxazolyl, oxadiazolyl,morpholinyl, sydnonyl, benzoxazolyl, benzoxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl, thienyl,dihydrodithiinyl, dihydrodithionyl, benzothiazolyl, benzothiadiazolyl,furyl, dihydrooxathiinyl, benzothienyl, benzodithiinyl andbenzoxathiinyl, and said acyl group may have from 1 to 10 substituentsselected from the group consisting of halogen, hydroxy, nitro, loweralkyl, amino, lower alkoxycarbonylamino, lower alkoxy, carboxy,N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl,phenylimino(lower)alkyl, lower alkanoyl, mono, di or trihalo(lower)alkyland phenylamino, or a salt thereof, or (3) subjecting a compound of theformula: ##STR14## wherein R¹, R², R_(a) ³ and A are each as definedabove, or a salt thereof to deacylation reaction to give a compound ofthe formula: ##STR15## wherein R¹, R² and A are each as defined above,or a salt thereof.
 8. A pharmaceutical composition which comprises, asan active ingredient, an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof in admixture withpharmaceutically acceptable carriers.
 9. A process of administering acholecystokinin antagonist to a patient comprising administering aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt to a patient in need thereof.
 10. A process of treatingor preventing cholecystokinin-mediated diseases which comprisesadministering an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof to a human or animal.